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Sex differences in kidney stone formation are well known. Females generally have slightly acidic blood and higher urine pH when compared with males, which makes them more vulnerable to calcium stone formation, yet the mechanism is still unclear. We aimed to examine the role of sex in stone formation during hypercalciuria and urine alkalinization through acetazolamide and calcium gluconate supplementation, respectively, for 4 weeks in wild-type (WT) and moderately hypercalciuric [TRPC3 knockout [KO](-/-)] male and female mice. Our goal was to develop calcium phosphate (CaP) and CaP+ calcium oxalate mixed stones in our animal model to understand the underlying sex-based mechanism of calcium nephrolithiasis. Our results from the analyses of mice urine, serum, and kidney tissues show that female mice (WT and KO) produce more urinary CaP crystals, higher [Ca 2+ ], and pH in urine compared to their male counterparts. We identified a sex-based relationship of stone-forming phenotypes (types of stones) in our mice model following urine alkalization/calcium supplementation, and our findings suggest that female mice are more susceptible to CaP stones under those conditions. Calcification and fibrotic and inflammatory markers were elevated in treated female mice compared with their male counterparts, and more so in TRPC3 KO mice compared with their WT counterparts. Together these findings contribute to a mechanistic understanding of sex-influenced CaP and mixed stone formation that can be used as a basis for determining the factors in sex-related clinical studies., (Published by Elsevier Inc.)

Regular transfusion and chelation therapy produces increased life expectancy in thalassaemic patients who may develop new complications. Since few data are available regarding hypercalciuria in β-thalassaemia major (TM), the aim of our study was to evaluate its prevalence, risk factors and clinical consequences. We enrolled 176 adult TM patients followed at the Center of Thalassemia of Ferrara. Hypercalciuria was defined by a calciuria of 4 mg/kg/day or more in a 24-h urine sample. Anamnestic, biochemical and radiological data were collected. Hypercalciuria prevalence was reported in 69.3% of patients (females 52.5%). Hypercalciuric (HC) patients used deferasirox (DFX) more often than normocalciuric (NC) patients (47.5% vs 29.6%; p < 0.05). In HC subjects plasma parathyroid hormone (PTH) (24.1 ± 10.4 vs 30.1 ± 13.2 pg/ml) and phosphate levels (3.6 ± 0.5 vs 3.8 ± 0.7 mg/dl) were lower, whereas serum calcium (9.6 ± 0.4 vs 9.4 ± 0.4 mg/dl) and urinary 24-h phosphaturia (0.9 ± 0.4 vs 0.6 ± 0.3 g/day) were higher as compared to NC patients (p < 0.05 for all comparisons). Supplementation with oral calcium and cholecalciferol was similar between the groups. A higher rate of kidney stones was present in HC (14.8%) versus NC patients (3.7%) (p < 0.05). Hypercalciuria is a frequent complication in adequately treated adult TM patients. Hypercalciuria prevalence is increased in DFX users whereas haemoglobin level or calcium supplements play no role. A significant proportion of HC patients developed kidney stones., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Urinary Stone Disease (USD) arises from an interaction of genetic and environmental factors. Urinary metabolic abnormalities are well described as risk factors. In Mexico, the Maya region holds the highest prevalence of USD. Treatment of these abnormalities lowers the risk of recurrences., Aim: Assess the underlying metabolic abnormalities of patients with USD to provide a rationale to lead further prevention strategies., Methods: Clinical and demographical data from patients coming to the Stone Clinic were prospectively collected along with a 24 h urinary panel to identify metabolic abnormalities. All participants signed consent and the study was approved by the hospital's institutional review board., Results: A total of 126 patients were included, with a mean age of 47.2 ± 13 years, 75.4% were female. A positive family history of stones was observed in 40 and 87.3% were overweight/obese. The frequency of hypocitraturia, hypercalciuria, hypomagnesuria, hyperoxaluria, and hyperuricosuria was 91.3, 68.5, 42.1, 36.5, and 26.6%, respectively. Median urinary citrate was 79.5 (37.5-160) mg/24 h and was inversely correlated to glycemia. Urine Calcium/Creatinine index was correlated with Hounsfield units (HU) (p = 0.01). Oxalate was correlated with HU and stone burden. Interestingly, dietary distribution of macro- and micronutrients were similar between groups. Patients with a single kidney had lower citrate and higher urinary calcium., Conclusions: Interestingly, a shortage of inhibitors such as citrate and magnesium are highly prevalent in patients with USD from the Maya region and seems to be influenced by other metabolic conditions as malnutrition next to the genetic component., Competing Interests: Declaration of Competing Interest Mario Basulto-Martínez declares that he has no conflict of interest. Barbara I Peña-Espinoza that she has no conflict of interest. Rafael Valdez-Ortiz that he has no conflict of interest. Rachel Escalante-Sosa that she has no conflict of interest. Juan P. Flores-Tapia that he has no conflict of interest. Marta Menjivar that she has no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Antibiotics can alter the gut microbiome (GMB), which may be associated with stone disease. We sought to determine the effect that antibiotics have on the GMB, urine ion excretion and stone formation in genetic hypercalciuric stone-forming (GHS) rats. 116th generation GHS rats were fed a fixed amount of a normal calcium (1.2%) and phosphate (0.65%) diet, and divided into three groups (n = 10): control (CTL) diet, or supplemented with ciprofloxacin (Cipro, 5 mg/day) or Bactrim (250 mg/day). Urine and fecal pellets were collected over 6, 12 and 18 weeks. Fecal DNA was amplified across the 16S rRNA V4 region. At 18 weeks, kidney stone formation was visualized by Faxitron and blindly assessed by three investigators. After 18 weeks, urine calcium and oxalate decreased with Bactrim compared to CTL and Cipro. Urine pH increased with Bactrim compared to CTL and Cipro. Urine citrate increased with Cipro compared to CTL and decreased by half with Bactrim. Calcification increased with Bactrim compared to CTL and Cipro. Increased microbial diversity correlated with decreased urinary oxalate in all animals (R = - 0.46, p = 0.006). A potential microbial network emerged as significantly associated with shifts in urinary pH. Bactrim and Cipro differentially altered the GMB of GHS rats. The Bactrim group experienced a decrease in urine calcium, increased CaP supersaturation and increased calcification. The GMB is likely a contributing factor to changes in urine chemistry, supersaturation and stone risk. Further investigation is required to fully understand the association between antibiotics, the GMB and kidney stone formation.

Background & Aims: Abnormalities of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) secretion may cause calcium-phosphate (Ca-P) metabolism disorders in nephrolithiasis. Post-phosphate-load alterations in serum Ca, P and PTH, phosphaturia and calciuria enable monitoring hormonal regulation of Ca-P homeostasis. Our study aimed to determine differences in: 1.selected Ca-P metabolism parameters between healthy and kidney-stone-forming individuals, 2.PTH and FGF23 secretion induced by sodium-phosphate-load(NaP-load) in patients with/without hypercalciuria, 3.secretion of Ca-P related hormones in patients with low and normal/high serum concentrations of 25-hydroxyvitamin D 3 (25OHD 3 )., Methods: Sodium phosphates NaH 2 PO 4 /Na 2 HPO 4 -100mmol were administered orally for five days in 19 hypercalciuric [urinary Ca(U-Ca) 6.5 ± 1.7 mmol/d]-HSF, 35 normocalciuric (2.5±1 mmol/d)-NSF stone-forming patients and 19 controls (U-Ca 2.5 ± 1.4 mmol/d)-CG. On days 1 and 5 PTH-,FGF23-,Ca-,P were determined before and after NaP-load. The areas under PTH, FGF23 curves (AUC) were calculated. U-Ca, urinary phosphate (U-P) and sodium (U-Na) were also determined., Results: Following NaP-load, patients and controls exhibited expected alterations in Ca-P homeostasis. Despite changes in phosphate and PTH, no differences in FGF23 concentrations were observed. Patients differed from controls in having higher AUCPTH, calciuria and natriuresis, taking longer for PTH and P to normalize and lack of correlation between AUCPTH and phosphaturia. Post-NaP-load hypocalciuric effect of PTH secretion in NSF was less pronounced than in CG. In the HSFs, the hypocalciuric effect was more pronounced than in NSFs, but insufficient to correct hypercalciuria. In all stone-formers with low 25OHD 3 concentrations, the AUCFGF23 was significantly increased on first (1215 ± 605vs766 ± 315 p = 0.0457) and fifth days (1211 ± 641vs777 ± 299 p = 0.041) of NaP-load, compared to normal/high 25OHD 3 -patients. Hypercalciuric patients with low 25OHD 3 concentrations had greater AUCPTH5 than those with normal/high 25OHD 3 (1005 ± 401vs835 ± 220 p = 0.0341)., Conclusions: Compared to controls, kidney-stone-forming patients exhibited enhanced PTH secretion after NaP-load. The HSFs showed a more pronounced hypocalciuric effect than NSFs, but insufficient to correct hypercalciuria. In hypercalciuric stone-formers with low 25OHD 3 , FGF23 engagement in hyperphosphatemia reduction increased., Competing Interests: Conflict of Interest All authors of this publication declare no conflicts of interests., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: The prevalence of kidney stones in children has significantly increased in the past few decades, with concomitant increased morbidity and healthcare costs worldwide. Assessing metabolic risk factors is essential for diagnosis and specific treatment. The objective of this retrospective study is to identify the epidemiological and clinical characteristics of children under 17 years of age, as well as the metabolic risk factors of nephrolithiasis., Methods: A total of 300 children with kidney stone disease were included to undergo several clinical tests using a standardized protocol., Results: The mean age was 11.2 years, and the male:female ratio was 1.15:1.0. Biochemical abnormalities were found in 89.3% of all cases. A single urine metabolic risk factor was present in 52.6% (n = 141) of the patients, and multiple risk factors were present in 36.7% (n = 106). Idiopathic hypercalciuria (alone or in combination) and hypocitraturia (alone or in combination) were the most frequent risk factors identified in 47.0% and 39.6% of these patients, respectively. Renal colic and/or unspecified abdominal pain were the most frequent forms of presentation (76.9%), followed by hematuria in 64.4% with 97.5% of stones located in the upper urinary tract. A positive family history in first-degree and second-degree relatives was found in 64.8% of boys and 61.8% of girls., Conclusions: We conclude that specific urinary metabolic risk factors can be found in most children with kidney stones, with hypercalciuria and hypocitraturia being the most common diagnoses. Graphical abstract .

The major risk factor for kidney stone disease is idiopathic hypercalciuria. Recent evidence implicates a role for defective calcium reabsorption in the renal proximal tubule. We hypothesized that claudin-2, a paracellular cation channel protein, mediates proximal tubule calcium reabsorption. We found that claudin-2-null mice have hypercalciuria due to a primary defect in renal tubule calcium transport and papillary nephrocalcinosis that resembles the intratubular plugs in kidney stone formers. Our findings suggest that a proximal tubule defect in calcium reabsorption predisposes to papillary calcification, providing support for the vas washdown hypothesis. Claudin-2-null mice were also found to have increased net intestinal calcium absorption, but reduced paracellular calcium permeability in the colon, suggesting that this was due to reduced intestinal calcium secretion. Common genetic variants in the claudin-2 gene were associated with decreased tissue expression of claudin-2 and increased risk of kidney stones in 2 large population-based studies. Finally, we describe a family in which males with a rare missense variant in claudin-2 have marked hypercalciuria and kidney stone disease. Our findings indicate that claudin-2 is a key regulator of calcium excretion and a potential target for therapies to prevent kidney stones.

Background: The incidence of nephrolithiasis in children and adolescents is increasing and appears to double every 10 years. The most important role of the pediatric nephrologist is to diagnose and modify various metabolic and non-metabolic risk factors, as well as prevent long-term complications especially in the case of recurrent nephrolithiasis., Objective: The purpose of this review is to summarize the existing literature on the etiology and management of pediatric nephrolithiasis., Results: The incidence of kidney stones is increasing; dietary and environmental factors are probably the main causes for this increased incidence. In most pediatric patients, the etiology for the kidney stones can be identified. Metabolic factors, such as hypercalciuria and hypocitraturia, urinary tract infection, and urinary stasis, constitute leading causes. Herein, we review the etiologies, diagnostic work-up, and treatment options for the most prevalent causes of kidney stones. The detrimental effects of excessive dietary sodium, reduced fluid intake, and the benefits of plant-based over animal-based protein consumption on urinary crystal formation are discussed. We also review the long-term complications., Conclusions: Pediatric nephrologists have an important role in the diagnostic work-up and prevention of recurring nephrolithiasis.

In stone formers (SFs) with idiopathic hypercalciuria, urine pH governs the mineral phase of stones. Calcium phosphate (CaP) SFs have higher urine pH than calcium oxalate (CaOx) SFs. Normal women have higher urine pH than men on fixed diets, accompanied by greater absorption of food alkali. Female CaP and male CaOx SFs have similar urine pH as same sex normal individuals, but male CaP and female CaOx SFs may have abnormal acid-base handling. We studied 25 normal individuals (13 men and 12 women), 17 CaOx SFs (11 men and 6 women), and 15 CaP SFs (8 men and 7 women) on fixed diets. Urine and blood samples were collected under fasting and fed conditions. Female CaOx SFs had lower urine pH and lower alkali absorption, fed, compared with normal women; their urine NH 4 was higher and urine citrate excretion lower than in normal women, consistent with their higher net acid excretion. Male CaOx SFs had higher urine citrate excretion and higher serum ultrafilterable citrate levels than normal men. Both male and female CaP SFs had higher urine pH fasting than same sex normal individuals, but only men were higher in the fed period, and there were no differences from normal in gut alkali absorption. CaP SFs of both sexes had higher urine NH 4 and lower urine citrate than same sex normal individuals. The lower urine pH of female CaOx SFs seems related to decreased gut alkali absorption, while the higher pH of CaP SFs, accompanied by higher urine NH 4 and lower urine citrate, suggests a proximal tubule disorder.

The expression of vitamin D receptor (VDR) and 1,25-dihydroxyvitamin D 3 [1,25(OH)D] levels exceed the values of controls in some but not all hypercalciuric stone formers (HSF). We aimed to evaluate serum 1,25(OH)D levels, the expression of VDR, CYP27B1, and CYP24A1 hydroxylases in HSF in comparison with normocalciuric stone formers (NSF) and healthy subjects (HS). Blood samples, 24-h urine collections and a 3-day dietary record were obtained from 30 participants from each of the groups. The expression of VDR, CYP27B1, and CYP24A1 was measured by flow cytometry. HSF presented significantly higher urinary volume, sodium, magnesium, oxalate, uric acid, and phosphorus than NSF and HS. Calcium intake was lower in HSF versus NSF and HS (442 ± 41 vs 594 ± 42 and 559 ± 41 mg/day, respectively, p = 0.027). Ionized calcium was significantly lower in HSF than NSF (1.29 ± 0.0 vs 1.31 ± 0.0 mmol/L, p < 0.01). Serum 1,25(OH)D was significantly higher in HSF and NSF than HS (22.5 ± 1.2; 22.2 ± 1.2 vs 17.4 ± 1.2 pg/ml, p = 0.007) but serum 25(OH)D, PTH, klotho and plasma FGF-23 did not differ between groups. VDR expression was higher in HSF and NSF than HS (80.8 ± 3.2; 78.7 ± 3.3 vs 68.6 ± 3.2%, p = 0.023). Although CYP27B1 and CYP24A1 expressions were similar among all groups, the ratio of 1,25(OH)D/CYP24A1 was higher in HSF and NSF than in HS (1.43 ± 0.25 and 0.56 ± 0.10 vs 0.34 ± 0.06, p = 0.00). Stone formers, regardless of urinary calcium excretion, had higher VDR expression and 1,25(OH)D levels than HS, even in ranges considered normal. Higher 1,25(OH)D/CYP24A1 ratio suggested a lower degradation of 1,25(OH)D by CYP24A1 in HSF and NSF.

Study Question: Can whole exome sequencing (WES) reveal a novel pathogenic variant in asthenozoospermia in a multiplex family including multiple patients?, Summary Answer: Patients were discovered to be homozygous for a rare 2-bp deletion in the ADCY10 coding region (c.1205&#95;1206del, rs779944215)., What Is Known Already: ADCY10 encodes for soluble adenylyl cyclase (sAC), which is the predominant adenylate cyclase in sperm. It is already established that proper sAC activity and a constant supply of cAMP are crucial to sperm motility regulation, and knockout mouse models have been reported as severely asthenozoospermic. ADCY10 is a susceptibility gene for dominant absorptive hypercalciuria (OMIM#143870); however, no ADCY10 variations have been confirmed to cause human asthenozoospermia to date., Study Design, Size, Duration: This was a retrospective genetics study of a highly consanguineous pedigree of asthenozoospermia. The subject family was recruited in Iran in 2016., Participants/materials, Setting, Methods: The two patients were diagnosed as asthenozoospermic through careful clinical investigations. Both patients, respective parents, and an unaffected brother were subjected to WES. The discovered variant was validated by Sanger sequencing and segregated with the phenotype. To confirm the pathogenicity of the variant, sperm samples from both patients, 10 normozoospermic men and 10 asthenozoospermic patients not representing the variation, were treated with a cAMP analogue dissolved in human tubal fluid medium, followed by computer-assisted sperm analysis and statistical analyses., Main Results and the Role of Chance: The discovered homozygous variant occurs at 10 amino acids upstream of the ADCY10 nucleotide binding site leading to a premature termination (p.His402Argfs*41). Treatment of the patients' sperm samples with a cell-permeable cAMP analogue resulted in a significant increase in sperm motility, indicating the pathogenic role of the variant. Moreover, absorptive hypercalciuria, segregating within the family, was also associated with the same variant following a dominant inheritance., Limitations, Reasons for Caution: Though nonsense-mediated decay is highly likely to occur in the mutated transcripts, we were not able to confirm this due to low RNA levels in mature sperm., Wider Implications of the Findings: Our finding enlarges the phenotypic spectrum associated with the ADCY10 gene, previously described as a susceptibility gene for dominant absorptive hypercalciuria., Study Funding/competing Interest(s): This study was supported by grants from the Royan Institute, Tehran, Iran, and San Raffaele Hospital, Milan, Italy. The authors have no conflict of interest., Trial Registration Number: N/A., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Kidney stone disease is characterized by a relatively high rate of recurrence. In our study we analyzed the association between relative supersaturation and the risk of stone recurrence. Additionally, we examined the association between the risk of recurrence and changes in relative supersaturation and urinary composition after 1 week of medical treatment., Materials and Methods: We performed a post hoc analysis of data from a previously published randomized controlled trial comparing the effect of 2 diets in 120 men with recurrent calcium oxalate stones and hypercalciuria. Baseline and followup 24-hour urine parameters were used to calculate the relative supersaturation of calcium oxalate, calcium phosphate and uric acid using the EQUIL2, JESS and LithoRisk computer programs. Cox models were used to calculate the estimated association between each baseline relative supersaturation, and 1-week changes and the risk of recurrence during followup., Results: During a 5-year followup 35 patients (34%) experienced recurrence. A reduction in calcium oxalate relative supersaturation at 1 week was significantly associated with a lower risk of recurrence using the EQUIL2 calculation (for every 10% reduction from baseline HR 0.92, 95% CI 0.86-1.00, p = 0.044). However, there was no association for relative supersaturation calculated by other methods or for the relative supersaturation of other salts. Changes in the 24-hour urine excretion of citrate, potassium and magnesium were significantly associated with a risk of recurrence., Conclusions: In recurrent stone formers with hypercalciuria baseline values and changes in the relative supersaturation of calcium oxalate may be associated with the risk of recurrence. Changes in urinary citrate, potassium and magnesium following dietary intervention may also be predictive., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: To study (1) the differences in the relative abundance of urinary proteins between children with kidney stones (RS) and hypercalciuria, hypocitraturia, normal metabolic work-up, and healthy controls (HC); (2) the association of these proteins with various diseases., Methods: Quantitative proteomic comparison of pooled urine from RS (N = 30, 24 females, mean age 12.95 ± 4.03 years) versus age- and gender-matched HC, using mass spectrometry. Relative protein abundance was estimated using spectral counting. Proteins of interest were selected using the following criteria: (1) ≥ 5 spectral counts; (2) ≥ twofold difference in spectral counts; and (3) ≤ 0.05 p value for the Fisher's Exact Test., Results: Of the 1813 proteins identified, 229 met the above criteria, with 162 proteins up-regulated in the RS group and 67 up-regulated in HC. The largest group of proteins (30 out of 229) was found to be associated with cardiovascular disease (CVD). Of those, 16 were involved in coagulation, fibrinolysis, and adhesion, 10 in inflammation, 5 in lipid transport and metabolism, and 4 in oxidative stress. All except two were exclusively found in children with hypercalciuria and hypocitraturia, and were not seen in children with normal metabolic work-up., Conclusion: Using a proteomic approach, we found a significant association between hypercalciuric and hypocitraturic nephrolithiasis and CVD in children. The shared risk factors among both diseases are endothelial dysfunction and atherosclerosis caused by abnormal coagulation, adhesion, disturbance of lipid transport and metabolism, oxidative stress and inflammation. Further understanding of the pathophysiological link between nephrolithiasis and CVD is necessary for developing new therapeutic targets.

Introduction and Objectives: Studies have demonstrated associations between nephrolithiasis and systemic conditions, including low bone mineral density (BMD), which may correlate with hypercalciuria in kidney stone formers (KSFs). Traditionally, low BMD is diagnosed with dual-energy X-ray absorptiometry. As a noncontrast CT (NCCT) scan is typically part of a stone evaluation, our objective was to evaluate the association of NCCT-based vertebral BMD with 24-hour urine parameters in KSF., Materials and Methods: This is a retrospective analysis of 99 KSFs who had CT imaging and 24-hour urine studies. For each patient, BMD was estimated at the L1 vertebral body and CT attenuation measured in HU. A threshold of 160 HU was chosen to distinguish normal from low BMD. Univariate and multivariate logistic regression analysis was performed to compare patients with low and normal BMD. Multivariate linear regression was performed to assess for variables associated with 24-hour urine parameters., Results: Patients with low BMD had higher 24-hour urine calcium (219 vs 147 mg/day, p < 0.0001) and larger stone volume (259 vs 78.4 mm 3 , p = 0.009). Multivariate analysis demonstrated age >60 years (odds ratio [OR] 9.3, p < 0.0001) and hypercalciuria (OR 4.34, p = 0.004) correlated with low BMD. Linear regression demonstrated that lower BMD was associated with higher urinary calcium (β-coefficient -0.268, p = 0.009) and lower urinary citrate (β-coefficient 0.332, p = 0.01)., Conclusions: CT-based diagnosis of low mineral bone density is associated with derangement in 24-hour urine calcium and citrate in KSFs, as well as larger stone volumes.

Hypercalciuria is a main risk factor for kidney stone  formation. TRPV5 is the gatekeeper protein for mediating calcium transport and reabsorption in the kidney. In the present study, we tested the effect of TRPV5 activation with small activating RNA (saRNA), which could induce gene expression by targeting the promoter of the gene, on ethylene glycol (EG)-induced calcium oxalate (CaOx) crystals formation in rat kidney. Five pairs of RNA activation sequences targeting the promoter of rat TRPV5 were designed and synthesized. The synthesized saRNA with the strongest activating effect was selected, and transcellular calcium transportation was tested by Fura-2 analysis. Subsequently, Sprague-Dawley rats were equally divided into three groups and fed with water, 1% EG for 28 days after injecting the negative control saRNA, 1% EG for 28 days after injecting the selected TRPV5-saRNA, respectively. The CaOx crystal formation and the 24-h urine components were assessed. In vitro study, saRNA ds-320 could significantly activate the expression of TRPV5 and transcellular calcium transportation. In vivo study, after 28 days treatment of EG, rats pre-infected with saRNA ds-320 had lower urinary calcium excretion and renal CaOx crystals formation as compared to that pre-infected with negative control saRNA. Activation of TRVP5 with saRNA ds-320 could inhibit EG-induced calcium oxalate crystals formation via promoting urine calcium reabsorption and decreasing urine calcium excretion in rats.

Purpose: The paper focuses on the relationship of risk factors and metabolic disorders with mineralogical composition of calculi, age and gender of calcium oxalate stone formers., Materials and Methods: Stone mineralogical composition, 24 hour biochemistry and pH-profile of urine were examined for sixty four stone formers using powder X-ray diffraction, spectrophotometric and potentiometric techniques., Results: The analysis indicated that 44 % of calculi were composed of pure calcium oxalate monohydrate, whereas other 56 % contained both monohydrate and dihydrate or usually their mixtures with hydroxyl apatite. Hypocitraturia, hypercalciuria and hyperuricosuria were identified as the most frequent disorders. Patients with pure calcium oxalate stones and calcium oxalate mixed with apatite revealed different patterns including age, acid-base balance of urine, calcium, citrate excretion etc.Conclusions: Our results demonstrate that most patients simultaneously reveal several risk factors. The special attention should be paid to normalize the daily citrate, calcium and urate excretion. High risk patients, such as postmenopausal females or stone formers with a high apatite content require a specific metabolic evaluation towards in highlighting abnormalities associated with stone formation.

The estimated lifetime risk of nephrolithiasis is growing nowadays, and the formation of kidney stones is frequently promoted by hypercalciuria. Vitamin D, and especially its active metabolite calcitriol, increase digestive calcium absorption-as urinary calcium excretion is directly correlated with digestive calcium absorption, vitamin D metabolites could theoretically increase calciuria and promote urinary stone formation. Nevertheless, there was, until recently, low evidence that 25-hydroxyvitamin D serum levels would be correlated with kidney stone formation, even if high calcitriol concentrations are frequently observed in hypercalciuric stone formers. Low 25-hydroxyvitamin D serum levels have been associated with a broad spectrum of diseases, leading to a huge increase in vitamin D prescription in the general population. In parallel, an increased frequency of kidney stone episodes has been observed in prospective studies evaluating vitamin D alone or in association with calcium supplements, and epidemiological studies have identified an association between high 25-hydroxyvitamin D serum levels and kidney stone formation in some groups of patients. Moreover, urinary calcium excretion has been shown to increase in response to vitamin D supplements, at least in some groups of kidney stone formers. It seems likely that predisposed individuals may develop hypercalciuria and kidney stones in response to vitamin D supplements., Competing Interests: The authors declare no conflict of interest.

While vitamin D (vitD) deficiency is thought to contribute to poor health in a variety of ways and should be corrected, there is still concern about giving vitD supplements to patients with a history of nephrolithiasis. The aim is to study the prevalence of vitD deficiency and the effect on stone risk of cholecalciferol (vitD3) supplementation in a cohort of idiopathic stone formers (ISF). We screened for vitD deficiency and urinary measures of stone risk, comparing vitD deficient (serum 25-OH vitD ≤30 nmol/L; ≤12 ng/mL) with vitD insufficient (31-75 nmol/L; 13-30 ng/mL) or vitD replete (>75 nmol/L; >30 ng/mL); we investigated the effect of giving vitD3 (20,000 IU orally, weekly for 4 months) to 37 of the vitD deficients. Thirty-one percent (142/456) were vitD deficient, 57% (259/456) vitD insufficient, and the rest (12%) vitD replete (55/456). Comparison among the groups showed that baseline 24-h urinary measures related to stone risk expressed as concentration ratios over urine creatinine (Cr), such as U. Calcium/Cr, U. Oxalate/Cr, U. Citrate/Cr, and U. Uric acid/Cr were not significantly different. VitD3 supplementation did significantly increase serum 25-OH vitD levels and U. Phosphate/Cr ratios, as well as reduce serum parathyroid hormone (PTH) concentrations. Following vitD3 supplementation, there was an overall rise in 24-h urine calcium excretion, but it failed to reach statistical significance (p = 0.06). U. Calcium/Cr increased in 22 out of 37 patients (average increase +0.07 mmol/mmol), decreased in 14 (average decrease -0.13 mmol/mmol), and remained unchanged in 1; 6 out of 26 initially normocalciuric ISF developed hypercalciuria; and 6 out of 9 patients who became vitD replete were hypercalciuric after supplementation. It is appropriate to monitor urinary Ca excretion in vitD-supplemented stone formers, because it may reveal underlying hypercalciuria in some treated patients.

Introduction and Objective: Despite guidelines, routine 24-hour urine testing is completed in <10% of high-risk, recurrent stone formers. Using surrogates for metabolic testing, such as key patient characteristics, could obviate the cost and burden of this test while providing information needed for proper stone prevention counseling., Methods: We performed a retrospective study of 392 consecutive patients from 2007 to 2014 with ≥2 lifetime stone episodes, >70% calcium oxalate by mineral analysis, and ≥1 24-hour urine collection. We compared mean 24-hour urine values by age in decades. We used logistic regression and receiver operating characteristic (ROC) curve analysis to assess the predictive ability of age, gender, body mass index (BMI), and comorbidities to detect abnormal 24-hour urine parameters., Results: The mean age of the cohort was 51 ± 16 years. Older age was associated with greater urinary oxalate (p-trend <0.001), lower urinary uric acid (UA) (p-trend = 0.007), and lower urinary pH (p-trend <0.001). A nonlinear association was noted between age and urinary calcium or citrate (calcium peaked at 40-49 years, p = 0.03; citrate nadired at 18-29 years, p = 0.001). ROC analysis of age, gender, and BMI to predict 24-hour urine abnormalities performed the best for hyperuricosuria (area under the curve [AUC] 0.816), hyperoxaluria (AUC 0.737), and hypocitraturia (AUC 0.740). Including diabetes mellitus or hypertension did not improve AUC significantly., Conclusions: In our recurrent calcium oxalate cohort, age significantly impacted urinary calcium, oxalate, citrate, and pH. Along with gender and BMI, age can be used to predict key 24-hour urine stone risk results. These data lay the foundation for a risk prediction tool, which could be a surrogate for 24-hour urine results in recurrent stone formers, who are unwilling or unable to complete metabolic testing. Further validation of these findings is needed in other stone populations.

Background: Using a proteomic approach, we aimed to identify and compare the urinary excretion of proteins involved in lipid transport and metabolism in children with kidney stones and hypercalciuria (CAL), hypocitraturia (CIT), and normal metabolic work-up (NM), and in healthy controls (HCs). Additionally, we aimed to confirm these results using ELISA, and to examine the relationship between the urinary excretion of selected proteins with demographic, dietary, blood, and urinary parameters., Methods: Prospective, controlled, pilot study of pooled urine from CAL, CIT, and NM versus age- and gender-matched HCs, using liquid chromatography-mass spectrometry. Relative protein abundance was estimated using spectral counting. Results were confirmed by ELISA performed on individual samples., Results: Of the 1,813 proteins identified, 230 met the above criteria. Of those, 5 proteins (apolipoprotein A-II [APOA2]; apolipoprotein A-IV [APOA4]; apolipoprotein C-III [APOA3]; fatty acid-binding protein, liver [FABPL]; fatty acid-binding protein, adipocyte [FABP4]) involved in lipid metabolism and transport were found in the CAL group, with significant differences compared with HCs. ELISA analysis indicated statistically significant differences in the urinary excretion of APOC3, APOA4, and FABPL in the CAL group compared with HCs. Twenty-four-hour urinary calcium excretion correlated significantly with concentrations of ApoC3 (r = 0.77, p < 0.001), and FABPL (r = 0.80, p = 0.005)., Conclusions: We provide proteomic data showing increased urinary excretion of lipid metabolism/transport-related proteins in children with kidney stones and hypercalciuria. These findings suggest that abnormalities in lipid metabolism might play a role in kidney stone formation.

Objective: Hypercalciuria is a common lithogenic risk factor. The aim of this study was, first, to study the characteristics of urine biochemical factors of children with hypercalciuria (HC) and compare them with those of children without hypercalciuria. Second, to analyze the differences between children with HC and lithiasis (HCL) and children with HC and no lithiasis (HCNL)., Methods: The sample was composed by 111 cases with HC, divided into 2 groups: HCNL group, consisting of 93 cases with no personal history of kidney stones, and HCL group, 18 cases with personal history of kidney stones. As a cohort control group, 113 healthy children were used. Creatinine, urea, sodium, potassium, chlorine, uric acid, calcium, phosphorus, magnesium and osmolality: blood and 24-hour urine following parameters were determined. Oxalate and citrate were determined in urine., Results: The mean values of natriuresis, uricosuria, phosphaturia, magnesuria, citraturia, calcium oxalate and calcium phosphate saturation were higher in HCNL than in control group. The HCL group had phosphaturia, calcium oxalate and calcium phosphate saturations more elevated compared with the control group. There were no significant differences in urinary excretion of various parameters when the groups HCL and HCNL were compared., Conclusions: Our results show that children with hypercalciuria without lithiasis associated show an increase in natriuresis, phosphaturia, uricosuria, magnesuria and citraturia. We found no differences between these urinary abnormalities when compared hypercalciuric children without lithiasis with those with hypercalciuria and urolithiasis.

Aim: One has to measure urinary enzymes and proteins to determine renal dysfunction and tubular injury in earlier stage during the course of disease. The aim of this study was to investigate the role of urinary NGAL (neutrophil gelatinase-associated lipocalin), IL-18 (Interleukin 18), and KIM-1 (kidney injury molecule-1) levels in determining early renal injury in pediatric patients with hypercalciuria (HC) and/or nephrolithiasis (NL) and to compare the levels of these markers between the sick and healthy subjects., Material and Methods: Urinary NGAL, KIM- 1, and IL- 18 levels were measured in 40 pediatric patients diagnosed with NL, 23 patients with HC, and 20 healthy controls., Results: A significant difference was found between patient groups (NL and HC) and healthy children with respect to urinary NGAL/cr ratio (p < 0.001). There were no significant differences between patient and control groups with respect to urinary IL18/cr and KIM1/cr ratios., Conclusions: We found that urinary NGAL is a useful marker for determining renal tubular damage in NL and HC. To our knowledge, this is the first study to report significantly increased urinary NGAL levels in NL and HC.

Potassium citrate is prescribed to decrease stone recurrence in patients with calcium nephrolithiasis. Citrate binds intestinal and urine calcium and increases urine pH. Citrate, metabolized to bicarbonate, should decrease calcium excretion by reducing bone resorption and increasing renal calcium reabsorption. However, citrate binding to intestinal calcium may increase absorption and renal excretion of both phosphate and oxalate. Thus, the effect of potassium citrate on urine calcium oxalate and calcium phosphate supersaturation and stone formation is complex and difficult to predict. To study the effects of potassium citrate on urine supersaturation and stone formation, we utilized 95th-generation inbred genetic hypercalciuric stone-forming rats. Rats were fed a fixed amount of a normal calcium (1.2%) diet supplemented with potassium citrate or potassium chloride (each 4 mmol/d) for 18 weeks. Urine was collected at 6, 12, and 18 weeks. At 18 weeks, stone formation was visualized by radiography. Urine citrate, phosphate, oxalate, and pH levels were higher and urine calcium level was lower in rats fed potassium citrate. Furthermore, calcium oxalate and calcium phosphate supersaturation were higher with potassium citrate; however, uric acid supersaturation was lower. Both groups had similar numbers of exclusively calcium phosphate stones. Thus, potassium citrate effectively raises urine citrate levels and lowers urine calcium levels; however, the increases in urine pH, oxalate, and phosphate levels lead to increased calcium oxalate and calcium phosphate supersaturation. Potassium citrate induces complex changes in urine chemistries and resultant supersaturation, which may not be beneficial in preventing calcium phosphate stone formation., (Copyright © 2015 by the American Society of Nephrology.)

Metabolic evaluation is important in high-risk patients with a history of urinary calculi, in order to prevent recurrence. This study aimed to compare patients with calcium calculi and mild lithogenic activity with those with moderate to severe lithogenic activity. Patients with moderate to severe activity had higher levels of urinary calcium level (271.9 mg/24h versus 172.1 mg/24 h, P < .001), uric acid (612.3 mg/24 h versus 528.9 mg/24h, P = .008), and fasting calcium-creatinine ratio (0.16 versus 0.12, P = .001) compared to those with mild lithogenic activity. No association was observed between lithogenic factors in 24-hour urine and mild lithogenic activity in multivariable analysis. We initially thought that in patients who develop recurrent calculi after 5 years or who have mild lithogenic activity, complete metabolic evaluation would not be necessary. However, based on our study findings, it may be important to conduct further studies assessing the lithogenic activity.

Nephrolithiasis is a frequent condition in urology that has an important recurrence and high impact in health economy. Knowing the biochemical abnormalities implicated in its pathogenesis is mandatory to establish therapeutic aims. Our objectives are to present the results in 3040 kidney stone formers in Argentina. All patients were selected after completing an ambulatory metabolic protocol with diagnostic purposes. There were 1717 men, (56.48%), with a mean age of 45±12 years, and 1323 women, (43.52%), mean age 44±12 years. 2781 patients had biochemical abnormalities, (91.49%), and were arbitrarily divided in two groups: those who had only one (single) biochemical abnormality (n=2156) and those who had associated abnormalities (n=625). No biochemical abnormalities were found in 259 patients (8.51%). The abnormalities present, single and associated, in order of frequency, were idiopathic hypercalciuria, (56.88%), hyperuricosuria (21.08%), unduly acidic urine (10.95%), hypocitraturia (10.55%), hypomagnesuria (7.9%), primary hyperparathyroidism (3.01%), hyperoxaluria (2.6%), and cystinuria (0.32%). We performed in 484 patient's stone composition and found calcium oxalate stones related to idiopathic hypercalciuria predominantly while uric acid stones to unduly acidic urine. In conclusion, the biochemical abnormalities described are similar to those found in a previous series of our own and to those reported in the literature. Its diagnosis is important to therapeutic purposes to avoid eventual recurrence.

Idiopathic hypercalciuria (IH) is a common familial trait among patients with calcium nephrolithiasis. Previously, we have demonstrated that hypercalciuria is primarily due to reduced renal proximal and distal tubule calcium reabsorption. Here, using measurements of the clearances of sodium, calcium, and endogenous lithium taken from the General Clinical Research Center, we test the hypothesis that patterns of segmental nephron tubule calcium reabsorption differ between the sexes in IH and normal subjects. When the sexes are compared, we reconfirm the reduced proximal and distal calcium reabsorption. In IH women, distal nephron calcium reabsorption is decreased compared to normal women. In IH men, proximal tubule calcium reabsorption falls significantly, with a more modest reduction in distal calcium reabsorption compared to normal men. Additionally, we demonstrate that male IH patients have lower systolic blood pressures than normal males. We conclude that women and men differ in the way they produce the hypercalciuria of IH, with females reducing distal reabsorption and males primarily reducing proximal tubule function., (Copyright © 2015 the American Physiological Society.)

Purpose: Recurrent kidney stones are associated with bone mineral density loss, altered bone remodeling markers, hypercalciuria and increased in fasting calcium/creatinine ratio. The objective was to determine biochemical alterations in urine in patients with osteopenia/osteoporosis without calcium kidney stones compared with patients with calcium kidney stones., Methods: This is a cross-sectional study including 142 patients who were divided in two groups: Group 1 (patients with recurrent calcium kidney stones) and Group 2 (patients with osteopenia/osteoporosis in the lumbar spine or hip). Analyses of bone mineral density, calcium-phosphorous and bone metabolism and lithogenic risk factors in fasting urine samples and 24-h urine samples were performed. Statistical analysis was carried out with SPSS 17.0. A p ≤ 0.05 was considered statistically significant., Results: Patients in Group 2 presented greater loss of bone mineral density and more elevated alkaline phosphatase, iPTH, phosphorous and β-crosslaps levels, as compared to patients in Group 1. However, Group 1 presented greater urine calcium, oxalate and uric acid and a higher proportion of hypocitraturia, hypercalciuria and hyperoxaluria, as compared to Group 2. Multivariate analysis revealed that advanced age and β-crosslaps levels are risk factors for bone mineral density loss, while low urinary calcium excretion was protective against bone demineralization., Conclusion: Patients with osteopenia/osteoporosis without lithiasis present some urinary biochemical alterations. This would explain the lack of lithogenic activity, although low calcium excretion in 24-h urine samples is a protective factor against the loss of bone mineral density.

Genetic hypercalciuric stone-forming (GHS) rats demonstrate increased intestinal Ca absorption, increased bone resorption, and reduced renal tubular Ca reabsorption leading to hypercalciuria and all form kidney stones. GHS have increased vitamin D receptors (VDR) at these sites of Ca transport. Injection of 1,25(OH)2D3 (1,25D) leads to a greater increase in urine (u)Ca in GHS than in control Sprague-Dawley (SD), possibly due to the additional VDR. In GHS the increased uCa persists on a low-Ca diet (LCD) suggesting enhanced bone resorption. We tested the hypothesis that LCD, coupled to inhibition of bone resorption by alendronate (alen), would eliminate the enhanced 1,25D-induced hypercalciuria in GHS. SD and GHS were fed LCD and half were injected daily with 1,25D. After 8 days all were also given alen until euthanasia at day 16. At 8 days, 1,25D increased uCa in SD and to a greater extent in GHS. At 16 days, alen eliminated the 1,25D-induced increase in uCa in SD. However, in GHS alen decreased, but did not eliminate, the 1,25D-induced hypercalciuria, suggesting maximal alen cannot completely prevent the 1,25D-induced bone resorption in GHS, perhaps due to increased VDR. There was no consistent effect on mRNA expression of renal transcellular or paracellular Ca transporters. Urine CaP and CaOx supersaturation (SS) increased with 1,25D alone in both SD and GHS. Alen eliminated the increase in CaP SS in SD but not in GHS. If these results are confirmed in humans with IH, the use of bisphosphonates, such as alen, may not prevent the decreased bone density observed in these patients.

Introduction: Topiramate (TPM), an anti-epileptic drug with >4 million users, increases renal stones in adults. We screened outpatient TPM-treated children without history of stones to estimate the prevalence of renal stones and to characterize urine stone-risk profiles., Methods: Children taking TPM ≥1 month underwent an interview, renal ultrasound, and spot urine testing in this prospective study. Normal spot urine values were defined as: calcium/creatinine ratio ≤0.20 mg/mg (>12 months) or ≤0.60 mg/mg (≤12 months), citrate/creatinine ratio >0.50 mg/mg, and pH ≤ 6.7., Results: Of 41 patients with average age of 9.2 years (range 0.5-18.7), mean TPM dose of 8.0 mg/kg/day (range 1.4-23.6), and mean treatment duration of 27 months (range 1-112), two (4.9%) had renal stones. The majority of children taking TPM had lithogenic abnormalities on spot urine testing, including 21 (51%) with hypercalciuria, 38 (93%) with hypocitraturia, and 28 (68%) with pH ≥ 6.7. Hypercalciuria and hypocitraturia were independent of TPM dose and duration; urine pH increased with dose. 24-h urine parameters improved in 1 stone-former once TPM was weaned., Conclusions: Asymptomatic stones were found in 2/41 (4.8%) children taking TPM. Risk factors for stones were present in the spot urine of most children, including hypocitraturia (93%) and hypercalciuria (51%), independent of TPM dose and duration. High urine pH, found in 68%, correlated with TPM dose. Pediatric specialists should be aware of increased risks for stones, hypercalciuria, hypocitraturia, and alkaline urine in children taking TPM., (Published by Elsevier Ltd.)

Context: Calcium stone formers with idiopathic hypercalciuria (IH) are known to exhibit an exaggerated postprandial rise in urine calcium excretion compared with non-stone-forming individuals, and insulin has been proposed to mediate this difference., Objective: Our objective was to investigate the impact of hyperinsulinemia on urine calcium excretion in IH compared with non-stone-forming controls., Participants and Setting: Ten IH patients and 22 control non-stone-forming subjects (8 lean and 14 overweight and obese) participated at the University of Texas Southwestern Clinical and Translational Research Center., Design: After stabilization on a fixed metabolic diet, subjects underwent a hyperinsulinemic-euglycemic clamp. Fasting 2-hour urine specimens were collected before and during the clamp., Main Outcome Measures: Changes in fractional calcium excretion (F(E)Ca) during the clamp were compared between the 3 groups of subjects (IH, overweight/obese controls, and lean controls). Insulin sensitivity was measured by glucose disposal rate., Results: IH had significantly higher 24-hour urine calcium excretion than controls, and exhibited similar age, body mass index, and insulin sensitivity as overweight/obese controls. The hyperinsulinemic-euglycemic clamp resulted in a significant increase in serum insulin with no significant changes in serum calcium and glucose. This was accompanied by a small increase in F(E)Ca, with no significant differences between the 3 groups. There was no correlation between insulin sensitivity and 24-hour urine calcium or the change in F(E)Ca during the hyperinsulinemic clamp., Conclusions: The rise in urine calcium associated with euglycemic hyperinsulinemia was small and not statistically different between IH and non-stone-forming controls. Insulin is therefore unlikely to play a significant pathogenetic role in IH.

The aim of this study is to investigate the effects of dietary factors on 24-hour urine parameters in patients with idiopathic recurrent calcium oxalate stones. A total of 108 of idiopathic recurrent calcium oxalate stones were included in the study. A 24-hour urinalysis was performed and metabolic abnormalities were measured for all of the patients. All of the patients were given specialized diets for their 24-hour urine abnormalities. At the end of first month, the same parameters were examined in another 24-hour urinalysis. Hyperoxaluria, hypernatruria, and hypercalciuria were found in 84 (77%), 43 (39.8%), and 38 (35.5%) of the patients, respectively. The differences between the oxalate, sodium, volume, uric acid, and citrate parameters before and after the dietary intervention were significant (p < 0.05). The calcium parameters were not significantly different before and after the intervention. We found that oxalate, sodium, volume, uric acid, and citrate-but not calcium-abnormalities in patients with recurrent calcium oxalate stones can be corrected by diet. The metabolic profiles of idiopathic calcium oxalate stone patients should be evaluated and the appropriate dietary interventions should be implemented to decrease stone recurrence., (Copyright © 2012. Published by Elsevier B.V.)

Calcium nephrolithiasis in children is increasing in prevalence and tends to be recurrent. Although children have a lower incidence of nephrolithiasis than adults, its etiology in children is less well understood; hence, treatments targeted for adults may not be optimal in children. To better understand metabolic abnormalities in stone-forming children, we compared chemical measurements and the crystallization properties of 24-h urine collections from 129 stone formers matched to 105 non-stone-forming siblings and 183 normal, healthy children with no family history of stones, all aged 6 to 17 years. The principal risk factor for calcium stone formation was hypercalciuria. Stone formers have strikingly higher calcium excretion along with high supersaturation for calcium oxalate and calcium phosphate, and a reduced distance between the upper limit of metastability and supersaturation for calcium phosphate, indicating increased risk of calcium phosphate crystallization. Other differences in urine chemistry that exist between adult stone formers and normal individuals such as hyperoxaluria, hypocitraturia, abnormal urine pH, and low urine volume were not found in these children. Hence, hypercalciuria and a reduction in the gap between calcium phosphate upper limit of metastability and supersaturation are crucial determinants of stone risk. This highlights the importance of managing hypercalciuria in children with calcium stones.

We have bred a strain of rats to maximize urine (u) calcium (Ca) excretion and model hypercalciuric nephrolithiasis. These genetic hypercalciuric stone-forming (GHS) rats excrete more uCa than control Sprague-Dawley rats, uniformly form kidney stones, and similar to patients, demonstrate lower bone mineral density. Clinically, thiazide diuretics reduce uCa and prevent stone formation; however, whether they benefit bone is not clear. We used GHS rats to test the hypothesis that the thiazide diuretic chlorthalidone (CTD) would have a favorable effect on bone density and quality. Twenty GHS rats received a fixed amount of a 1.2% Ca diet, and half also were fed CTD (4 to 5 mg/kg/d). Rats fed CTD had a marked reduction in uCa. The axial and appendicular skeletons were studied. An increase in trabecular mineralization was observed with CTD compared with controls. CTD also improved the architecture of trabecular bone. Using micro-computed tomography (µCT), trabecular bone volume (BV/TV), trabecular thickness, and trabecular number were increased with CTD. A significant increase in trabecular thickness with CTD was confirmed by static histomorphometry. CTD also improved the connectivity of trabecular bone. Significant improvements in vertebral strength and stiffness were measured by vertebral compression. Conversely, a slight loss of bending strength was detected in the femoral diaphysis with CTD. Thus results obtained in hypercalciuric rats suggest that CTD can favorably influence vertebral fracture risk. CTD did not alter formation parameters, suggesting that the improved vertebral bone strength was due to decreased bone resorption and retention of bone structure., (Copyright © 2011 American Society for Bone and Mineral Research.)

Patients with idiopathic hypercalciuria (IH) and genetic hypercalciuric stone-forming (GHS) rats, an animal model of IH, are both characterized by normal serum Ca, hypercalciuria, Ca nephrolithiasis, reduced renal Ca reabsorption, and increased bone resorption. Serum 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels are elevated or normal in IH and are normal in GHS rats. In GHS rats, vitamin D receptor (VDR) protein levels are elevated in intestinal, kidney, and bone cells, and in IH, peripheral blood monocyte VDR levels are high. The high VDR is thought to amplify the target-tissue actions of normal circulating 1,25(OH)(2)D levels to increase Ca transport. The aim of this study was to elucidate the molecular mechanisms whereby Snail may contribute to the high VDR levels in GHS rats. In the study, Snail gene expression and protein levels were lower in GHS rat tissues and inversely correlated with VDR gene expression and protein levels in intestine and kidney cells. In human kidney and colon cell lines, ChIP assays revealed endogenous Snail binding close to specific E-box sequences within the human VDR promoter region, whereas only one E-box specifically bound Snail in the rat promoter. Snail binding to rat VDR promoter E-box regions was reduced in GHS compared with normal control intestine and was accompanied by hyperacetylation of histone H(3). These results provide evidence that elevated VDR in GHS rats likely occurs because of derepression resulting from reduced Snail binding to the VDR promoter and hyperacetylation of histone H(3)., (Copyright 2010 American Society for Bone and Mineral Research.)

Background: A direct relation exists between sodium and calcium excretion, but randomized studies evaluating the sustained effect of a low-salt diet on idiopathic hypercalciuria, one of the main risk factors for calcium-oxalate stone formation, are still lacking., Objective: Our goal was to evaluate the effect of a low-salt diet on urinary calcium excretion in patients affected by idiopathic calcium nephrolithiasis., Design: Patients affected by idiopathic calcium stone disease and hypercalciuria (>300 mg Ca/d in men and >250 mg Ca/d in women) were randomly assigned to receive either water therapy alone (control diet) or water therapy and a low-salt diet (low-sodium diet) for 3 mo. Twenty-four-hour urine samples were obtained twice from all patients: one sample at baseline on a free diet and one sample after 3 mo of treatment., Results: A total of 210 patients were randomly assigned to receive a control diet (n = 102) or a low-sodium diet (n = 108); 13 patients (2 on the control diet, 11 on the low-sodium diet) withdrew from the trial. At the follow-up visit, patients on the low-sodium diet had lower urinary sodium (mean +/- SD: 68 +/- 43 mmol/d at 3 mo compared with 228 +/- 57 mmol/d at baseline; P < 0.001). Concomitant with this change, they showed lower urinary calcium (271 +/- 86 mg/d at 3 mo compared with 361 +/- 129 mg/d on the control diet, P < 0.001) and lower oxalate excretion (28 +/- 8 mg/d at 3 mo compared with 32 +/- 10 mg/d on the control diet, P = 0.001). Urinary calcium was within the normal range in 61.9% of the patients on the low-salt diet and in 34.0% of those on the control diet (difference: +27.9%; 95% CI: +14.4%, +41.3%; P < 0.001)., Conclusion: A low-salt diet can reduce calcium excretion in hypercalciuric stone formers. This trial was registered at clinicaltrials.gov as NCT01005082.

Idiopathic hypercalciuria is the most important predisposing risk factor for calcium oxalate (CaOx) renal stone formation. We assessed the associations between spontaneous CaOx crystallization based on the Bonn Risk Index (BRI), urinary pH, calciuria, oxaluria, and citraturia in 140 Caucasian patients with hypercalciuria, aged 4-17 years, and compared the findings with those in 210 normocalciuric controls. Of the 140 hypercalciuric patients, 58 had renal stones, and 82 had recurrent erythrocyturia, renal colic, or urinary obstructive symptoms-but without stones. Urinary ionized calcium ([Ca(2+)]) levels were measured using a selective electrode, while the onset of crystallization was determined using a photometer and titration with 40 mmol/L ammonium oxalate (Ox(2-)). The calculation of the BRI was based on the [Ca(2+)]:Ox(2-) ratio. The BRI values were 12-fold higher in hypercalciuric children than in healthy controls, but no differences were found in the BRI between subjects with urinary stones and those with urolithiasis-like symptoms. An increased BRI suggested an association with hypercalciuria, lower urinary pH, hypocitraturia, and hypooxaluria. These data indicate that hypercalciuria is an important factor associated with increased urinary CaOx crystallization, although the causal pathways need further investigation. Determination of the BRI in children with hypercalciuria may improve the risk assessment of kidney stones.

The evaluation of metabolic risk factor in children with renal stone disease is the basis of medical treatment aimed at preventing recurrent stone events and the growth of preexisting calculi. In this retrospective study, we evaluated the metabolic risk factors and clinical and family histories of 90 children with kidney stone disease who had been referred to our institution and subjected to clinical tests using a standardized protocol. The mean age of our pediatric patients was 10.7 years, and the male:female ratio was 1.14:1.0. Biochemical abnormalities were found in 84.4% of all cases. A single urine metabolic risk factor was present in 52.2% (n = 47) of the patients, and multiple risk factors were present in the remaining 31.1% (n = 28). Idiopathic hypercalciuria (alone or in combination) and hypocitraturia (alone or in combination) were the most frequent risk factors identified in 40 and 37.8% of these patients, respectively. Renal colic or unspecified abdominal pain were the most frequent forms of presentation (76.9%), with 97.5% of stones located in the upper urinary tract. In most patients, stone disease was confirmed by renal ultrasonography (77%). A positive family history in first-degree and second-degree relatives was found in 46.2 and 32.5% of the cases, respectively. We conclude that specific urine metabolic risk factors are found in most children with kidney stones and that hypocitraturia is as frequent as hypercalciuria. Very often there is a positive family history of renal stone disease in first- and second-degree relatives.

Because urine ion excretion varies throughout the day, clinicians monitor 24 h urine samples to measure ion excretion and supersaturation in kidney stone patients. However, these results are averages and may not reflect maximal supersaturation which drives stone formation. We measured ion excretion and saturation in genetic hypercalciuric stone-forming rats on both a normal or low calcium diet over 0-3, 3-6 and 6-24 h using two feeding protocols, where the daily food allotment was fed either as a bolus or divided into three portions. With a normal calcium diet, urine calcium, oxalate, volume, and calcium oxalate supersaturation were significantly greater on the bolus compared to the divided feeds in the prandial and postprandial periods. Bolus eaters also excreted more calcium and oxalate and had increased volume over 24 h. Maximal calcium oxalate supersaturation was greater during the initial time periods than during the entire 24 h, regardless of the feeding schedule. With the low calcium diet, the effect of bolus feeding was reduced. Thus, urine ion excretion and supersaturation vary with the type of feeding. If these results are confirmed in man, it suggests that eating as a bolus may result in greater prandial and postprandial calcium oxalate supersaturation. This may increase growth on Randall's plaques and promote stone disease.

Increased urinary calcium excretion commonly is found in patients with hypertension and kidney stone disease (KSD). This study investigated the aggregation of hypertension and KSD in families of patients with KSD and hypercalciuria and explored whether obesity, excessive weight gain, and diabetes, commonly related conditions, also aggregate in these families. Consecutive patients with KSD, aged 18 to 50 yr, were recruited from a population-based Kidney Stone Center, and a 24-h urine sample was collected. The first-degree relatives of eligible patients (n = 333) and their spouse were interviewed by telephone to collect demographic and health information. Familial aggregation was assessed using generalized estimating equations. Multivariate-adjusted odds ratios (OR) revealed significant associations between hypercalciuria in patients and hypertension (OR 2.9; 95% confidence interval 1.4 to 6.2) and KSD (OR 1.9; 95% confidence interval 1.03 to 3.5) in first-degree relatives, specifically in siblings. No significant associations were found in parents or spouses or in patients with hyperuricosuria. Similarly, no aggregation with other conditions was observed. In an independent study of siblings of hypercalciuric patients with KSD, the adjusted mean fasting urinary calcium/creatinine ratio was significantly higher in the hypertensive siblings compared with normotensive siblings (0.60 +/- 0.32 versus 0.46 +/- 0.28 mmol/mmol; P < 0.05), and both sibling groups had significantly higher values than the unselected study participants (P < 0.001). Urinary sodium/creatinine and uric acid/creatinine ratios were not different among the groups. Although an environmental effect cannot be excluded fully, our findings suggest that the disturbance in calcium metabolism in hypertension and KSD has a genetic basis.